Kluge commanded the 4th Army at the opening of Operation Barbarossa, where he developed a strained relationship with Heinz Guderian over tactical issues in the advance, accusing Guderian of frequent disobedience of his orders. On 29 June Kluge ordered that, ‘Women in uniform are to be shot.’[1]

After Fedor von Bock was relieved of his command of Army Group Center in late 1941, Kluge was promoted and led that army group until he was injured in October 1943. Kluge frequently rode in an airplane to inspect the divisions under his command and sometimes relieved his boredom during the flights by shooting foxes from the air[2]—a decidedly non-traditional method. On 30 October 1942 Kluge was the beneficiary of an enormous bribe from Hitler, who mailed him a letter of good wishes together with a huge cheque made out to him from the German treasury and a promise that whatever improving his estate might cost could be billed out to the German treasury.[3] Kluge took the money, but after receiving severe criticism from his Chief of Staff, Henning von Tresckow, who upbraided him for corruption, he agreed to meet Carl Friedrich Goerdeler in November 1942.[4] Kluge promised Goerdeler that he would arrest Hitler the next time he came to the Eastern Front, but then after receiving another "gift" from Hitler he changed his mind and decided to stay loyal.[5] Hitler, who seems to have heard that Kluge was dissatisfied with his leadership, regarded his "gifts" as entitling him to Kluge's total loyalty.[5] On 27 October 1943 Kluge was badly injured when his car overturned on the Minsk–Smolensk road. He was unable to return to duty until July 1944. After his recovery he became commander of the German forces in the West (Oberbefehlshaber West) as Gerd von Rundstedt’s replacement.

Between June and July 1944, during the invasion of Normandy by Allied forces, Rommel commanded Army Group B under Field Marshal von Rundstedt. Rommel was charged with planning German counterattacks intended to drive the Allied forces back to the beaches. On 5 July Kluge replaced Rundstedt, because Rundstedt was advocating negotiation with the Allies. Two weeks later, Rommel was wounded and Kluge took over as commander of Army Group B as well, where Kluge's forces around the town of Falaise were encircled by combined U.S., Canadian, British, and Polish armies.

In August, after the failed coup attempt by Stauffenberg, Kluge was recalled to Berlin and replaced by Model.

Kluge's nickname among the troops and his fellow officers was der kluge Hans ("Clever Hans"). This nickname was acquired early in his career, partly in admiration of his cleverness and partly as a pun on his name (klug is German for "clever"). The "Hans" component came not from any of his given names but from Clever Hans, a horse which became famous for its apparent ability to do arithmetic.

A leading figure of the German military resistance, Henning von Tresckow, served as his Chief of Staff of Army Group Centre. Kluge was somewhat involved in the military resistance.[dubious– discuss] He knew about Tresckow’s plan to shoot Hitler during a visit to Army Group Centre, having been informed by his former subordinate, Georg von Boeselager, who was now serving under Tresckow. At the last moment, Kluge aborted Tresckow's plan. Boeselager later speculated that because Heinrich Himmler had decided not to accompany Hitler, Kluge feared that without eliminating Himmler too, it could lead to a civil war between the SS and the Wehrmacht.[6]

When Stauffenberg attempted to assassinate Hitler on 20 July, Kluge was Oberbefehlshaber West ("Supreme Field Commander West") with his headquarters in La Roche-Guyon. The commander of the occupation troops of France, General Carl-Heinrich von Stülpnagel, and his colleague Colonel Cäsar von Hofacker – a cousin of Stauffenberg – came to visit Kluge. Stülpnagel had just ordered the arrest of the SS units in Paris. Kluge had already learned that Hitler had survived the assassination attempt and refused to provide any support. "Ja – wenn das Schwein tot wäre!" ("Yes – if the pig were dead!)" he said.[7] On 17 August he was replaced by Walter Model and recalled to Berlin for a meeting with Hitler after the coup failed; thinking that Hitler would punish him as a conspirator, he committed suicide by taking cyanide near Metz two days later on 19 August. He left Hitler a letter in which he advised him to make peace, and to show "the greatness that will be needed to put an end to a hopeless struggle." Hitler reportedly handed the letter to Alfred Jodl and commented that "There are strong reasons to suspect that had not Kluge committed suicide he would have been arrested anyway."[8] SS officer Jürgen Stroop boasted of his involvement in investigating Kluge for involvement in the plot. He claimed to have offered the Field Marshal the opportunity to commit suicide, but that Kluge refused. He then claimed to have personally shot him and that Himmler had ordered him to announce that Kluge had committed suicide.[9]